Human immunodeficiency virus (HIV) is the pathogen that causes the acquired immunodeficiency syndrome (AIDS). According to WHO, globally, there were an estimated 33 million people living with HIV in 2007. The annual number of new HIV infections was 2.5 million last year, or an increase of about 6800 daily. Regionally, sub-Saharan Africa and under-developed Asia countries are still home to most of the people living with HIV.
HIV is one member of Lentivirus genus of the Retroviridae family. Up to now, the epidemic thereof can only be retarded but not terminated; effective antiretroviral therapy can only slow down the development of the disease, while cannot completely eliminate the virus. Moreover, it remains financially unaffordable for those who reside in the developing countries. It is thus widely believed that an effective vaccine is the only solution to restrain the global HIV-1 epidemic.
Anti-HIV candidate vaccines currently under investigation include: attenuated viable vaccines, deactivated vaccines, DNA vaccines, viable vector vaccines, subunit vaccines and protein vaccines. With respect to the development history of anti-HIV vaccines, they can be divided into 4 generations. The first generation (1980s) of HIV candidate vaccines was mainly based on protein subunit concept. These candidates are capable of inducing neutralizing antibodies, but not cytotoxic T lymphocytes. The second generation (1990s) vaccine is based on the concept of recombinant vectors, especially using virus vectors followed by boosting with subunit recombinant vaccines. This concept is theoretically very attractive because preliminary data suggest that these vaccines induce both humoral and cell-mediated immunity. However, these vaccines have failed to protect vaccines from HIV infection. The third generation (2000-2005) of HIV candidate vaccines was based on the feature of different vaccine vectors and strategy to proceed carefully to expanded phase II and phase III trials to assess the protective efficacy of these candidate vaccines in humans. The new concept is based on inducing potent immune response by HIV conserved epitopes.
The HIV-1 envelope glycoprotein is the primary target for neutralization, and great efforts have been made to enhance the immunogenicity of Env in AIDS vaccine design. However, the Env glycoproteins frequently change their sequence in response to selective pressure exerted by the immune system, thus presenting the host with ever new antigens (Parren P W, et al. The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity. AIDS 1999.13 (Suppl A):S137-162). Furthermore, the trimeric Env structure shields important domains of the Env core, making them inaccessible to antibody-mediated neutralization. Conformational Env re-orientation upon CD4 receptor binding transiently uncovers neutralization-sensitive regions for coreceptor binding until the viral envelope fuses with the host cell membrane In addition, heavy glycosylation on the outside of gp120 hides much of the protein core from antibody attack (Kwong P D, et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 2002. 420:678-682). In all, the HIV Env protein poses a great challenge for generating broad reactive neutralizing antibodies. To induce a potent and cross-reactive neutralizing antibody, an effective envelope immunogen must be modified for HIV vaccine
Because of the lack of suitable animal model for HIV in nature, and human cannot be used for challenging test, people then turn to other six animal Lentivirus that belong to the same genus with HIV for relevant researches. Wherein, equine infectious anemia virus (EIAV) belongs to the same genus with HIV, and they both have same genome structures, replication modes, and similar protein categories and functions. It has been found that the V1, V2 regions of HIV-1 have a certain corresponding relations with the V3, V4 regions of EIAV (Hotzel I. Conservation of the human immunodeficiency virus type 1 gp120 V1/V2 stem/loop structure in the equine infectious anemia virus (EIAV) gp90. AIDS Res Hum Retroviruses, 2003, 19:923-924; and Huiguang Li, et al. A Conservative Domain Shared by HIV gp120 and EIAV gp90: Implications for HIV Vaccine Design. AIDS Res Hum Retroviruses, 2005, 21:1057-1059).
But due to the clear differences in the underlying mechanisms of pathogenesis of the two viruses, and which is different with HIV, the primary investigation process of attenuated EIAV vial vaccine is attenuation rather than the process of increasing immunogenicity. Hence, this alteration approach is all along despised by researchers in HIV vaccine development.
Based on the sequence analysis of the EIAV virulent strain and vaccine strain, and also based on the characteristic amino acid mutations of attenuated EIAV vial vaccine, the inventor utilized the approach of structurally and functionally corresponding positions to perform alterations for corresponding amino acid positions in HIV-1 envelope protein. Surprisingly, the altered antigenic polypeptide of HIV-1 envelope protein and vaccines constructed based on the polypeptide can induce the production of anti-HIV neutralizing antibodies with high tier, broad spectrum and persistence.